Promoter methylation in a mixed feedback loop circadian clock model

TL;DR

This paper extends a circadian clock model by including promoter methylation and reversible protein sequestration, analyzing their effects on oscillation stability and period control, revealing methylation's dual role in rhythm regulation.

Contribution

It introduces a novel extended model incorporating methylation and sequestration, providing new insights into their impact on circadian oscillations.

Findings

Methylation influences the period of circadian oscillations.

Excessive methylation can eliminate rhythmicity.

The model approximates a modified Goodwin oscillator.

Abstract

We introduce and analyze an extension of the mixed feedback loop model of Fran\c{c}ois and Hakim. Our extension includes an additional promoter state and allows for reversible protein sequestration, which was absent from the original studies of the mixed feedback loop model. Motivated by experimental observations that link DNA methylation with circadian gene expression, we use our extended model to investigate the role of DNA methylation(s) in the mammalian circadian clock. We extend the perturbation analysis of Fran\c{c}ois and Hakim to determine how methylation affects the presence and the periodicity of oscillations. We derive a modified Goodwin oscillator model as an approximation to show that although methylation contributes to period control, excessive methylation can abolish rhythmicity.